A 51-year-old man developed painless enlargement of the bilateral submandibular and lacrimal glands without xerostomia or xerophthalmia in the absence of autoantibodies to SS-A (Ro) and SS-B (La). In a few years, he developed generalized lymphadenopathy, with markedly elevated serum IgG4, and a computed tomography scan revealed soft-tissue-density lesions around the abdominal aorta, a finding consistent with retroperitoneal fibrosis. Biopsy of the cervical lymph node showed an expansion of the interfollicular area by heavily infiltrating plasma cells, consistent with multicentric Castleman's disease. Immunohistochemical analysis revealed that the IgG4-positive/IgG-positive plasma cell ratio was 80%, leading us to a single diagnosis of IgG4-related disease. High-dose corticosteroid treatment resulted in prompt resolution of the physical, serological, and imaging abnormalities. Although IgG4-related disease can mimic multicentric Castleman's disease, as in our patient, the two diseases have effective but distinct treatments, and thus measurement of serum IgG4 levels and specific immunohistochemical analysis for determining the IgG4-positive/IgG-positive plasma cell ratio are recommended if IgG4-related disease is suspected.